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Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126-5p in control of endothelial cell function in angiogenesis.

Abstract：

:MicroRNAs are small non-coding RNAs that negatively regulate posttranscriptional gene expression. Several microRNAs have been described to regulate the process of angiogenesis. Previously, we have shown that bone morphogenetic protein 4 (BMP4) increased the pro-angiogenic activity of endothelial cells. In this project, we now investigated how the pro-angiogenic BMP4 effect is mediated by microRNAs. First, we performed a microRNA array with BMP4-stimulated human umbilical vein endothelial cells (HUVECs). Among the top-regulated microRNAs, we detected a decreased expression of miR-494 and increased expression of miR-126-5p. Next, we analysed the canonical Smad and alternative signalling pathways, through which BMP4 would regulate miR-126-5p and miR-494 expression. Furthermore, the functional effect of miR-494 and miR-126-5p on endothelial cells was investigated. MicroRNA-494 overexpression decreased endothelial cell proliferation, migration and sprout formation. Consistently, miR-494 inhibition increased endothelial cell function. As potential miR-494 targets, bFGF and BMP endothelial cell precursor-derived regulator (BMPER) were identified and confirmed by western blot. Luciferase assays showed direct miR-494 binding in BMPER 3'UTR. In contrast, miR-126-5p overexpression increased pro-angiogenic endothelial cell behaviour and, accordingly, miR-126-5p inhibition decreased endothelial cell function. As a direct miR-126-5p target we identified the anti-angiogenic thrombospondin-1 which was confirmed by western blot analysis and luciferase assays. In the Matrigel plug assay application of antagomiR-494 increased endothelial cell ingrowth, whereas antagomiR-126-5p treatment decreased cell ingrowth in vivo. Taken together, through differential regulation of the anti-angiomiR-494 and the angiomiR-126-5p by BMP4 both microRNAs contribute to the pro-angiogenic BMP4 effect on endothelial cells.

journal_name

Thromb Haemost

journal_title

Thrombosis and haemostasis

authors

Esser JS,Saretzki E,Pankratz F,Engert B,Grundmann S,Bode C,Moser M,Zhou Q

doi

10.1160/TH16-08-0643

subject

Has Abstract

pub_date

2017-04-03 00:00:00

pages

734-749

issue

eissn

0340-6245

issn

2567-689X

pii

16-08-0643

journal_volume

117

pub_type

杂志文章

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Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126-5p in control of endothelial cell function in angiogenesis.